Diabetes, specifically the Type II (NIDDM) variety, has emerged in the twenty-first century as an epidemic of global proportions. Numerous long-term complications, including those affecting the kidneys, legs, feet, eyes, heart, nerves, and blood circulation, may result from uncontrolled diabetes. Prevention of these conditions requires comprehensive treatment, requiring life style modification and medication. A number of effective anti-diabetic drugs are available and are generally safe and well tolerated. All the medications become less effective as the disease progresses, and most patients eventually require insulin. Most of the medications are associated with risks of hypoglycemia and weight gain, yet do not alter the inexorable progression of diabetes.
Orally-delivered formulations for protein-based drugs such as insulin are being developed by the present inventor (Ziv et al 1994; Nissan et al 2000, Kidron et al 2004, Eldor et al 2010B, Eldor et al 2010C). One such oral insulin product is scheduled to be tested in Phase II trials and is currently being reviewed for IND status.
The incretin hormone Glucagon-like Peptide 1 (GLP-1), secreted within minutes of food ingestion, is associated with induction of insulin release. Therapies based on GLP-1 are treatment options for Type 2 Diabetes Mellitus (T2DM) that act through a variety of complementary mechanisms. The most intriguing aspect of the incretins is the fact that they cause insulin release in a glucose-dependent manner and are thought to have a low risk of inducing hypoglycemia. Furthermore, the incretins seem to be weight-neutral (or weight-reducing), preserve beta-cell mass, and possibly also induce neogenesis of insulin-secreting cells.
However, clinical use of the native GLP-1 is limited due to its rapid enzymatic inactivation, resulting in a half-life of 2-3 minutes. To overcome this obstacle, long-acting degradation-resistant peptides, both natural and synthetic, referred to as GLP-1 mimetic agents or analogues, have been designed and tested.
To date, GLP-1 analogues are only available as injectable dosage forms. The present inventor is developing an oral exenatide GLP-1 analogue capsule. A first-in-humans trial (n=4) testing its safety in healthy humans demonstrated retained biological functionality of orally delivered exenatide (Eldor et al 2010A).